A primary focus of drug research is the development of analgesics for pain management. Analgesics render sensory pathways insensible or less sensible to pain, whereas anesthetics act on all sensory pathways rendering them insensible to pain, temperature, touch, proprioception and skeletal muscle tone. As such, although anesthetics can be used for pain management, their utility is limited by their inhibition of these other sensory pathways. For example, it may be desired to control a patient's pain associated with an oral mucosal lesion without interfering with senses of touch, proprioception (to avoid biting of the tongue) or taste (so as not to interfere with appetite), which is not generally possible with topical anesthetics (for example, Benzocaine) which are not able to selectively inhibit pain. The use of analgesics to control pain in such circumstances is therefore desirable.
Analgesics are generally classified as either narcotic (opioids) or non-narcotic. Narcotic analgesics primarily act on the central nervous system and carry potentially life-threatening side-effects such as addiction, impaired higher cortical function and depressed respiration. As a result, their use is regulated and they may only be prescribed by licensed practitioners. Non-narcotic analgesics include salicylates, such as aspirin; acetaminophen; and non-steroidal anti-inflammatory drugs (“NSAIDS”), such as cyclooxygenase-2 (“Cox-2”) inhibitors. Such non-narcotic analgesics can be limited in their ability to control pain and may have the side effects of chemical irritation, anticoagulation, myocardial infarction and stroke. Accordingly, there is a continuing need for the discovery and development of new analgesics, and in particular non-narcotic analgesics, that are useful for the localized management of pain without an undesirable side effects profile.
In this regard, various plant-derived compounds have been investigated for their analgesic properties. For example, capsaicin, a vanillyl alkaloid that is the source of pungency in hot peppers, has been used to treat the pain of arthritis, osteoarthritis, and various peripheral neuropathies. See, for example, Cordell and Araujo, The Annals of Pharmacotherapy, (1993) 27:330; Levinson, (January/February 1995) The Sciences, pp. 13-15. However, the therapeutic usefulness of capsaicin is limited due to an adverse side effects profile that includes burning sensations and erythema, and such side effects may persist over time. By way of further example, extracts of sweet bell peppers (Capsicum annuum) have been shown to exhibit analgesic properties (see, for example, U.S. Pat. Nos. 6,060,060 and 6,086,888), but the specific compounds responsible for such analgesic effects have not been identified. Furthermore, as such extracts must be derived from naturally-occurring fruit, their production and practical use is limited.
Moreover, certain capsianosides (diterpene glycosides) that occur naturally in sweet bell peppers have been identified, for example capsianosides A-F and I-V reported both by Izumitani et al. (“Novel Acyclic Diterpene Glycosides, Capsianosides A-F and I-V from Capsicum Plants” (Solanaceous Studies, XVI) Chem. Pharm. Bull. (1990), 38(5):1299-1307) and by Iorizzi et al. (“New Glycosides from Capsicum annuum L. Var. acuminatum. Isolation, Structure Determination, and Biological Activity” J. Agric. Food Chem. (2001), 49:2022-2029), some of which have been shown to inhibit the activity of angiotensin-converting enzyme in vitro, and therefore may be useful as anti-hypertensive agents (see, for example, published Japanese Patent Application No. 02-138289 (1990)). However, no experimental or clinical data is known to have been reported that establishes the therapeutic utility of such compounds.